Zoledronic acid and pamidronate are potent bisphosphonates (BP) that have been associated with increased risk of osteonecrosis of the jaw (ONJ) in cancer patients. Sporadic spontaneous reports of ONJ among osteoporotic users of oral bisphosphonates have also been documented, raising questions about the public health consequences of prolonged BP use. ONJ affects morbidity and mortality statistics as well as the quality of life of oncologic patients. Preliminary studies suggest a prevalence rate of 4-10% among the exposed, but more studies are needed to elucidate the exact prevalence, time course, and etiology of the necrotic process. The genetic predisposition to the development of ONJ is not adequately understood; pharmacogenetic studies are needed to explain the inter-individual variation in bisphosphonate safety. The primary aim of this exploratory study is to stimulate research on the molecular epidemiology, etiology and prevention of ONJ, with a long-term vision to develop effective pharmacogenetic screening tools for risk assessment. If a genetic screening test is developed to identify those in risk of developing ONJ, the favorable risk benefit ratio of bisphosphonates will be maintained. The proposed exploratory clinical R21 award aims to pilot test case-control recruitment and specimen collection methods and to evaluate the biobanked materials in a limited, focused comparison of candidate genes. To enroll subjects with valid, narrowly defined phenotypes, we propose to a) assess the prevalence and time course of ONJ in hospital records of oncologic patients who have been treated with BPs since 2002, b) examine eligible patients to identify additional asymptomatic cases, c) validate the phenotype by means of medical record review and/or patient interviews as needed, d) pilot test the recruitment mechanism, assess participation and the specimen collection rate. We propose to build collaborations nationwide with a wide range of experts to facilitate plans for a large follow up study, and finally to study a select number of candidate genes for ONJ predisposition controlling for confounders (especially glycocorticosteroids, concomitant chemotherapeutics, and radiotherapy). Experience from the study's implementation and its preliminary data will allow the investigators to establish an adequate foundation for an expanded clinical research project, with appropriate sample size to allow for high throughput genotyping and advanced analytics to identify involved pathways and gene-gene interactions. Strengths of the proposed exploratory plan are the participation of clinical centers of excellence, the multi-disciplinary expertise of the co-investigators with their unique clinical, epidemiological, and basic genetic perspectives, and the PD/PIs prior experience in molecular epidemiology as well as in the analysis of large databases on issues of ONJ. [unreadable] [unreadable] [unreadable]